An Efficacy, Pharmacokinetics, Safety and Tolerability Study of TMC435 as Part of a Treatment Regimen for Hepatitis C-Infected Patients

• ClinicalTrials.gov Identifier: NCT01725529
• Recruitment Status: Completed
• First Posted: November 14, 2012
• Results First Posted: August 13, 2015
• Last Update Posted: August 13, 2015
• Sponsor: Janssen R&D Ireland
• Information provided by (Responsible Party): Janssen R&D Ireland

Study Description

Brief Summary:

The purpose of this study is to provide confirmatory efficacy and safety data of TMC435 as part of a treatment regimen including peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) in patients with genotype 1 Hepatitis C virus (HCV) infection.

Condition or disease	Intervention/treatment	Phase
Hepatitis C, Chronic	Drug: TMC435; Drug: Peginterferon-alpha (PegIFNα-2a); Drug: Ribavirin (RBV); Drug: Placebo	Phase 3

Detailed Description:

This is a multicenter, randomized (study drug is assigned by chance), double-blind (neither sponsor, physician nor patient knows the name of the assigned study drug), Phase III study to compare the efficacy, tolerability and safety of TMC435 (in development for treatment of chronic hepatitis C virus [HCV] infection) versus placebo (a preparation containing no drug used as control) as part of a treatment regimen including peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) (both current therapies for HCV) in adult treatment-naïve patients (patients who have never taken HCV medications) with genotype 1 Hepatitis C virus (HCV) infection. The study will consist of a screening period with a maximum duration of 6 weeks, a response guided 24- or 48-week (TMC435 treatment groups) or 48-week (control group) treatment period, and a post-therapy follow-up period up to 72 weeks after the start of treatment. Patients will be randomly assigned in a 1:1:1 fashion to receive TMC435 or placebo, stratified by HCV genotype 1 subtype and IL28B genotype within each country. In the first 24 weeks, patients will receive 12 weeks TMC435 100 or 150 mg or placebo once-daily (q.d.) plus PegIFNα-2a plus RBV, after which they will continue with PegIFNα-2a and RBV. Response-guided treatment criteria will be used to determine PegIFNα-2a and RBV total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. In the control group, all patients will be required to complete 48 weeks of treatment with PegIFNα-2a and RBV. In all 3 treatment groups, there will be a post-therapy follow-up period up to 72 weeks after the start of treatment. The total study duration for each patient will be a maximum of 78 weeks (including the 6-week screening period).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 457 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve, Genotype 1 Hepatitis C-Infected Subjects
• Study Start Date: November 2012
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: November 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: TMC435 150 mg; Patients will receive 12 weeks TMC435 150 mg once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV), followed by PegIFNα-2a and RBV alone. Response-guided treatment criteria will be used to determine total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. Patients in the control group will continue to receive treatment with PegIFNα-2a and RBV until Week 48.	Drug: TMC435; TMC435 100 mg or 150 mg capsules taken orally (by mouth) with food once-daily for 12 weeks (Week 12).; Drug: Peginterferon-alpha (PegIFNα-2a); PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.; Drug: Ribavirin (RBV); Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.
Experimental: TMC435 100 mg; Patients will receive 12 weeks TMC435 100 mg once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV), followed by PegIFNα-2a and RBV alone. Response-guided treatment criteria will be used to determine total treatment duration of 24 or 48 weeks for patients in the TMC435 treatment groups. Patients in the control group will continue PegIFNα-2a and RBV until Week 48.	Drug: TMC435; TMC435 100 mg or 150 mg capsules taken orally (by mouth) with food once-daily for 12 weeks (Week 12).; Drug: Peginterferon-alpha (PegIFNα-2a); PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.; Drug: Ribavirin (RBV); Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.
Placebo Comparator: Control; Patients will receive placebo once daily (q.d.) plus peginterferon-alpha (PegIFNα-2a) and ribavirin (RBV) for 48 weeks.	Drug: Peginterferon-alpha (PegIFNα-2a); PegIFNα-2a (180 micrograms [μg] once weekly) administered as weekly subcutaneous (s.c.) (under the skin) injections of 0.5 mL for 24 or 48 weeks.; Drug: Ribavirin (RBV); Ribavirin 1000 or 1200 mg/day (taken as 100 mg or 200 mg tablets) depending on body weight (If body weight is < 75 kg the total daily dose of RBV will be 1000 mg, administered as 400 mg intake with food in the morning and 600 mg intake with food in the evening. If body weight is > or = 75 kg the total daily dose will be 1200 mg, administered as 2 x 600 mg per intake with food, morning and evening) for 24 or 48 weeks.; Drug: Placebo; Matching placebo capsules taken orally with food once-daily for 48 weeks.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12) [ Time Frame: 12 weeks after the end of treatment (EOT: Week 24 or 48) ]
   Participants considered to have achieved SVR12 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ; 25 international unit per milliliter [IU/mL]) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 12 weeks after the planned end of study drug treatment.

Secondary Outcome Measures :

1. Percentage of Participants With Sustained Virologic Response 24 Weeks After End of Study Drug Treatment (SVR24) [ Time Frame: 24 weeks after the end of treatment (EOT: Week 24 or 48) ]
   Participants considered to have achieved SVR24 if both conditions are met: 1). the hepatitis C virus ribonucleic acid (HCV RNA) is less than (<) lower limit of quantification (LLOQ;25 IU/mL) undetectable at end of treatment and, 2). the HCV RNA is < LLOQ detectable or undetectable at 24 weeks after the planned end of study drug treatment.
2. Percentage of Participants With Sustained Virologic Response at Week 72 (SVRW72) [ Time Frame: Week 72 ]
3. Percentage of Participants With On-treatment Failure [ Time Frame: End of Treatment (EOT: Week 24 or 48) ]
   A participant with on-treatment failure refers to a participant with confirmed detectable HCV RNA at the end of treatment.
4. Percentage of Participants With Viral Breakthrough [ Time Frame: Week 24 or 48 (End of Treatment) ]
   The number of patients who experience viral breakthrough will be determined by measuring Hepatitis C virus (HCV) ribonucleic acid (RNA) levels in plasma. Viral breakthrough was defined as a confirmed increase of >1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of >100 IU/mL in subjects whose HCV RNA levels had previously been below the limit of quantification (<25 IU/mL detectable) or undetectable (<25 IU/mL undetectable) while on study treatment.
5. Percentage of Participants With Viral Relapse [ Time Frame: 72 weeks after the EOT (Week 24 or 48) ]
   Viral relapse was defined as undetectable HCV RNA at the actual end of treatment and last HCV RNA measurement during follow-up ≥25 IU/mL.
6. Percentage of Participants With On-treatment Normalization of Alanine Aminotransferase Level [ Time Frame: 72 weeks after the EOT (Week 24 or 48) ]
   Percentage of participants with on-treatment normalization of alanine aminotransferase level were assessed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• A liver biopsy within 3 years prior to the screening visit (or between screening and day of randomization) with histology consistent with chronic Hepatitis C virus (HCV) infection
• Presence of contraindications for a liver biopsy in patients who are otherwise deemed eligible for participation does not exclude the patient from participation
• Genotype 1 HCV infection (confirmed at screening)
• Plasma HCV RNA of > 10,000 IU/mL at screening

Exclusion Criteria:

• Prior treatment with any approved or investigational drug for the treatment of hepatitis C
• Co-infection with hepatitis B virus or human immunodeficiency virus (HIV)

Contacts and Locations

Locations

China

Beijing, China

Changchun, China

Changsha, China

Chengdu, China

Chongqing, China

Guangzhou, China

Hangzhou, China

Harbin, China

Jinan, China

Lanzhou, China

Nanjing, China

Shanghai, China

Shenyang, China

Tianjin, China

Wuhan, China

Zhengzhou, China

Korea, Republic of

Busan, Korea, Republic of

Chuncheon, Gangwon-Do, Korea, Republic of

Gyeongsangnam-Do, Korea, Republic of

Incheon, Korea, Republic of

Seoul, Korea, Republic of

Sponsors and Collaborators

Janssen R&D Ireland

Investigators

• Study Director: Janssen R&D Ireland Clinical Trial; Janssen R&D Ireland

More Information

• Responsible Party: Janssen R&D Ireland
• ClinicalTrials.gov Identifier: NCT01725529
• Other Study ID Numbers: CR017962; TMC435HPC3005 ( Other Identifier: Janssen R&D Ireland )
• First Posted: November 14, 2012
• Results First Posted: August 13, 2015
• Last Update Posted: August 13, 2015
• Last Verified: July 2015

Keywords provided by Janssen R&D Ireland:

Hepatitis C, Chronic; TMC435; Ribavirin; peginterferon-alpha (PegIFNα-2a)

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Hepatitis, Chronic; Ribavirin; Simeprevir; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Protease Inhibitors; Enzyme Inhibitors